The overall goal of this project is to define the mechanisms by which chronic intermittent hypoxia (CIH) affects O2 sensing ability of the carotid body. This proposal is based on our preliminary data suggesting that: a) CIH enhances the sensory response of the carotid body to hypoxia and induces prolonged activation of the baseline sensory activity resembling the phenomenon of long-term facilitation (LTF) in respiratory motor output; b) 5- HT receptor blockers prevent LTF in the sensory discharge but not the enhanced hypoxic sensitivity; and c) comparable duration of sustained hypoxia (SH) neither enhances the response to hypoxia nor induces LTF in the sensory discharge. These observations indicate that: 1) episodic pattern of hypoxia is more potent than continuous hypoxia in affecting carotid body function; and 2) the mechanisms by which CIH affects the hypoxic sensitivity of the carotid body seem to differ from those that induce LTF in the baseline activity. The current proposal tests two primary hypotheses: 1) the CIH-induced increase in hypoxic sensitivity of the carotid body involves alterations in internal calcium concentration homeostasis in glomus cells and/or down regulation of inhibitory transmitter(s) and/or increase in number of glomus cells; and 2) 5- HT mechanisms are critical for CIH-induced LTF in the sensory discharge in the carotid body. Experiments in Aim 1 define the factors that contribute to CIH-induced heightened sensitivity and to the induction of LTF in the carotid body. Experiments proposed in Aim 2, test whether alterations in internal calcium concentration homeostasis in glomus cells, and/or down-regulation of inhibitory neurotransmitters such as nitric oxide (NO), and/or an increase in the number of glomus cells (putative O2 sensing cells) contribute to the heightened chemosensitivity of the carotid body. In Aim 3, we will test the idea that 5-HT dependent mechanisms play a critical role in induction of LTF in the carotid body. Experiments in Aim 4 determine whether CIH-induced increases in hypoxic sensitivity and LTF in baseline sensory activity of the carotid body are translated to changes in ventilation. This project is thematically linked to Projects 18, 14, 19, 16, and 20. In addition, it has collaborative interactions from Drs. Katz, Kunze, Dick, and Kumar. The ventilatory data derived from this project will be incorporated into mathematical model utilizing Core 9007 facilities.